1. Field of the Invention
The invention pertains to a preparation for use of specific protein and/or peptide fractions having a high aspartate content for regulating plasma glucose concentrations and increasing insulin sensitivity in a mammal.
2. Description of the Related Art
Hyperglycaemia is a metabolic state of the body wherein glucose levels in blood are increased compared to normal concentrations in blood of about 3.9-6.1 mMol/l (70-110 mg per 100 ml). In times of starvation or after consumption of high amounts of glucose, these normal values tend to be outside this range, but the mammalian body has several mechanisms available to maintain glucose homeostasis.
Persons suffering from abnormally high glucose levels after consumption of a source of glucose are defined to suffer from a “high post-prandial glucose response” or to be “glucose intolerant”. Impaired glucose tolerance can result in increased glucose levels after fasting and is often associated with impaired glucose metabolism. Important examples can be found in persons that are diagnosed to suffer from the so-called metabolic syndrome or syndrome X, obesity and several types of diabetes, like type I, type II and gestational diabetes. Also persons that are under high emotional stress and patients that experienced severe trauma, surgery or that suffer from an acute illness, for example those that are accepted in the Intensive Care Units (ICU) in a hospital, demonstrate impaired capacity to control their blood glucose levels to levels below 6.1 mMol/l, which is probably due to the action of stress hormones like cortisol. Apart from these groups, also persons having certain types of inherited errors in metabolism, e.g. persons suffering from propionic academia, isovaleric academia, methylmalonic academia, oxoacid coenzyme A thiolase deficiency or deficiencies in the activity of other thiolases, and persons that have an underdeveloped metabolic system like young infants often experience periods with high post-prandial glucose levels in blood.
High post-prandial glucose responses can lead to a plurality of negative effects on health and body function, especially when it occurs for longer times or when it is associated with increased glucose levels after starvation. Examples of such negative effects are cardiovascular problems, both on a micro- and macrovascular level, problems with impaired eye-sight, renal problems, neurological problems like neuropathy and cognitive impairment, increased sensitivity to infections like those caused by yeasts, metabolic problems, and more acute effects like polyuria and feelings of excessive thirst and hunger.
Insulin plays a critical role in the functioning of the body and in particular in the metabolism of glucose in the body. Contrary to glucagon, insulin increases the uptake of glucose by peripheral cells, like those in skeletal muscle, and fat tissue, and in liver, pancreas and cardiac muscle, and it decreases hepatic gluconeogenesis. Insulin is released by the pancreas after consumption of food, in particular of food that comprises a source of glucose or protein. The release of insulin can be imparted when the pancreas has been severely damaged, e.g. during diabetes type I or pancreatitis. This will after some time result in severe health problems, especially when the decreased postprandial release of insulin occurs in combination with a decreased sensitivity to insulin. Insulin that is released then does not lead to increased absorption of glucose by the cells, in particular by the peripheral cells in the body like the muscle cells. This is also called “insulin resistance”.
Apart from diabetics there are many other groups of persons that suffer from insulin resistance, like many obese persons and persons that suffer from the metabolic syndrome. Also after severe trauma or surgery and during the severe stages of several diseases like cancer and AIDS, net insulin resistance is frequently observed. Insulin resistance leads to severe health problems, especially on the longer term, and increases morbidity and mortality risks in such patients.
Despite high systemic levels of glucose during hyperglycaemia, several tissues may still suffer from low levels of intracellular glucose. In order to maintain intracellular energy homeostasis, lipids or proteins will under such conditions be used as energy source. In cases wherein insufficient amounts of lipids or proteins are consumed, or in situations wherein body stores of lipids are not metabolised properly, catabolism of lean body mass occurs. During energy malnutrition severe complications may occur, especially when loss of lean body mass has progressed. Therefore a need exists for a nutritional product which increases insulin sensitivity in energy-malnourished persons, like those patients that experience severe diseases, persons who are strongly obese and/or in particular in the malnourished diabetic patient.
Neonates and in particular preterm babies often suffer from underdeveloped metabolic systems, which need to adapt in a short time to a new nutritional regimen. During the first few days and even weeks dramatic changes occur in their body for example with regard to expression of enzymes, organ capacity e.g. of the liver, pancreas, gut and kidneys and gut content. When nutritional practices are not adapted to their metabolic capabilities, disorders and diseases can be observed such as abnormally high or low levels of glucose in the blood.
In the Western world the prevalence of obesity and diabetes has been rising considerably over the last decades and even children have become susceptible to these diseases or disorders.
Many approaches have been described in the prior art to find nutritional products which prevent that glucose levels in plasma become too low but at the same time decrease postprandial glucose response and/or that decrease insulin resistance.
Nutritional products have been developed that decrease hyperglycemic response after consumption thereof. For example, the postprandial glucose response is claimed to be flattened by including a slowly digestible carbohydrate source, or the digestion rate is decreased by including fibres. Also, the glucose source can be replaced by another ingredient which releases alternative carbohydrates like fructose, which does not directly result in increased glucose levels in the blood after consumption. An example hereof is given in WO-A-03/105882. However, often the unique metabolic and physiological properties of glucose are not met adequately and these alternative carbohydrates, especially fructose, are suspected of having undesired side effects, especially at high dosages, like causing diarrhea, hyperuricaemia, imparting temporarily hepatic energy stores and causing an inflammatory response.
Another approach in the art is to adapt the protein composition in order to increase insulin release. In particular fortification with arginine, but also leucine, glycine or phenylalanine has been advocated for this purpose. The problem of insulin resistance is however not solved by this approach. The release of even more insulin challenges the already highly stressed pancreas and thus does not seem to be a very efficient approach. In addition, it is believed that the prevalence of high plasma levels of insulin during longer periods of time increases the risk of becoming obese and developing insulin resistance at a later age. This is particularly important for patients that suffer from problems with the pancreas and some specific problems with the liver, such as during diabetes type I, pancreatitis, cirrhosis and hepatitis.
Most commercially available complete nutritional products for diabetics have a protein fraction based on casein or soy. A better post-prandial glucose responses is especially attributed to soy-based products. Disadvantages of products in which the protein fraction is predominantly formed from soy is that the soy taste is not very appreciated and also provides a non-optimal amino acid profile to meet all requirements, e.g. on the amount of essential amino acids, for persons that suffer from hyperglycaemia, especially in case of a malnourished patient suffering from a low lean body mass and requiring strong anabolism during a prolonged period of time.
U.S. Pat. No. 6,706,697 discloses a diabetic and weight loss composition formulated as powder for preparing a drink comprising about 15 wt % fructose and 10 wt % insulin, and wherein the protein fraction of the drink is an organoleptically more acceptable combination of about 44 wt % isolated soy protein and 20 wt % milk protein isolate. Milk protein isolate has been defined as a spray dried, soluble casein and whey proteins isolated from fresh skim milk, wherein the combination of casein and whey proteins is obtained from simultaneous isolation of all proteins present in milk, yielding a mixture of casein and whey of 80:20, providing about 8 wt % of aspartate equivalents. Disadvantageously, the use of high amounts of fructose as suggested in U.S. Pat. No. 6,706,697 may result in the aforementioned unwanted side effects.
US 2004/0043013 discloses a composition of agents for metabolic uncoupling therapy comprising one or more members of at least 4 groups of agents. Examples 3-5 disclose preparations which are useful in achieving weight loss, treating hyperlipidaemia and the inhibition of Type II diabetes, respectively. These preparations consist largely of L-aspartic acid in combination with creatine, pyruvate and arginine, respectively. These preparations provide no essential amino acids and no source of glucose equivalents is included. Moreover, US 2004/0043013 teaches to consume large amounts of amino acids having drawbacks associated therewith. Creatine can have a deleterious effect on some enzymes of the trans-sulfuration pathways, the relatively expensive pyruvate easily decomposes in liquid formulae and is therefore not an attractive ingredient for use in nutritions, and arginine heavily stimulates the insulin release with the associated problems of putting stress on the pancreas and increasing the risk of developing insulin resistance.
Considering the magnitude of the aforementioned health problems and the low success rate of the solutions that have been disclosed in the prior art, a need exists for nutritional preparations or a dietetic regimen, which is easy to comply with, because of their enjoyable organoleptic properties, which fits in normal day life and feeding/drinking practices, avoids additional stress for the pancreas, maybe even relieves the task of the pancreas, has no undesired side effects and normalizes blood levels of glucose, especially after consumption of food and increases sensitivity to insulin.